Project Summary/Abstract Hawaii has the highest life expectancy at birth in the U.S.; however, health varies substantially within the State as Native Hawaiians experience worse health outcomes, reflected by a higher prevalence of obesity, type-2 diabetes (T2D) and other chronic diseases. The prevalence of obesity and T2D for Native Hawaiians are 2.0 and 2.3 times that of Whites, respectively. Further, obesity and T2D are complex disorders influenced by genetics and environmental factors, and their interactions across the life-course. Recent genome-wide association studies (GWAS) revealed that genetic variants were associated with higher risk of obesity and T2D. Individuals carrying some risk genes exhibit a markedly increased preference for high fat, but a significantly reduced preference for high sucrose food. However, the genetic evidence is mainly restricted to those of European descent and some Asian ethnic groups. There is a significant gap in our knowledge of genetic risks for Native Hawaiians and minority populations. And, the mechanisms underlying genetic predisposition to obesity and T2D and how lifestyle characteristics interact with genes remain obscure for Native Hawaiians, as well as other high-risk groups. Therefore, this proposed two-year study of secondary data from the Multiethnic cohort study of Diet and Cancer (MEC) aims to identify genetically predisposed risk groups and modifiable behavioral risk factors among Native Hawaiians and other minority ethnic groups living in Hawaii and California. We will first perform GWAS studies to identify genetic risk variants that are associated with obesity and T2D. Utilizing the identified risk genes, we will generate genetic ?barcode? and cluster subjects into various personalized genetic ?barcode? patterns. Then the genetic ?barcode? patterns and neighborhood socio-economic status will be incorporated into mixed models as cross-classified random effects to examine how our genetic patterns interact with diet and physical activities, individual socioeconomic status for all MEC racial/ethnic groups. The proposed study will provide a molecular basis for generating clinically useful classifications of obesity and T2D and will therefore contribute to identify new targets for pharmaceutical or behavioral interventions. It may lead to improved understanding of the role of epigenetics, such as DNA methylation, as a mediator of life-course gene-environmental interactions. Building upon this R21 funding, our long-term goal is to obtain R01 funding to support the collection of methylation data and perform epigenome- wide methylation studies (EWAS) of obesity and T2D. Combined results from GWAS and EWAS studies will significantly improve our understanding of the disease pathophysiology with implications for better-tailored public health interventions.